Fine-mapping Of The Major Histocompatibility Complex Region Linked To Leprosy In Northern China

BackgroundLeprosy is a chronic infectious disease caused by Mycobacterium leprae,which affects the skin and nervous system.Different methods in genetic research have been applied to the study of leprosy,which shows that leprosy is closely related to the genetic background of the host.Today,leprosy is one of the infectious diseases with the most genetic risk variation identified.Some leprosy genes are related to the host’s immune response to pathogens and point to specific pathways related to the host’s defense against infection.In addition,host genetic factors are also related to the heterogeneity of clinical manifestations of leprosy and the excessive inflammatory response in some leprosy patients.A large number of studies have shown that the risk of leprosy infection is closely related to the variation in human leukocyte antigen（HLA）region.HLA region not only affects the susceptibility of leprosy,but also affects the progress and outcome of leprosy.Due to the complex characteristics of HLA region,such as high polymorphism,linkage disequilibrium and haplotype inheritance,the study of HLA region has always been a difficult problem in leprosy genetics.HLA genotyping imputation,also HLA imputation,is a widely used method of fine mapping research.Based on the genome wide association study（GWAS）data,a variety of databases are jointly applied,which further improves the utilization and value of data sequencing,and has been successfully applied to a variety of diseases.ObjectivesThis study plans to carry out HLA imputation on HLA regions in GWAS data of Han leprosy population in northern China,so as to find independent leprosy loci in HLA regions,study the found loci,and further explore the variation and potential mechanism of HLA affecting the development of Han leprosy in northern China.MethodsThe genotyping of HLA region in GWAS data of Northern Han Chinese population（1238 leprosy patients and 1363 controls）was extracted for HLA imputation.Using1000 Genomes Project phase 3 dataset as the reference database and beagle 4.1 as the software,single-nucleotide polymorphisms（SNP）,insertion and deletion（INDEL）and copy number variant（CNV）imputation were carried out.HLA classical alleles and amino acids in the MHC region were imputed using the HAN-MHC database.After imputation,quality control was carried out for all loci,and stepwise regression analysis was carried out by Plink software.Three online websites（Regulome DB,Haplo Reg and r Var Base）were used to predict the bioinformatics function of variants to leprosy.ResultsFour independent variation loci of leprosy in Han nationality of northern China were identified:esv3608598(P=2.18×10^-25;OR=1.98;95%CI 1.74-2.25),rs7754498(P=2.75×10^-9,OR=1.42,95%CI 1.27-1.60),rs3130781(P=9.25×10^-8,OR=1.6,95%CI 1.34-1.90)and rs144388449(P=8.25×10^-7,OR=0.69,95%CI 0.60-0.80).Esv3608598 is a CNV deletion and the first HLA CNV found to be associated with leprosy risk.SNP rs7754498 is located 32 KB downstream of HLA-DRB5,SNP rs3130781 is located in the intron region of DPCR1,and SNP rs144388449 is located 8KB upstream of MICB.The software show that the three SNPs will affect the occurrence and development of leprosy in terms of gene transcription and expression.ConclusionThrough HLA imputation analysis of leprosy population of Han nationality in northern China,we found the leprosy related CNV variant esv3608598 and three new SNP independent loci related to leprosy risk（rs7754498,rs3130781 and rs144388449）.This result enriches the genetic variation results of leprosy research,provides a new idea for the inheritance and immunity of leprosy,and provides a basis for the follow-up HLA research.